Foot disorders affect approximately 20-60% of Americans and are increasingly linked to chronic mobility limitations and disability. Although the importance of genetics is commonly suspected, no linkage, candidate gene association, or genome-wide association studies (GWAS) on foot disorders have been performed. Our preliminary data from the Framingham Foot Study (an ancillary of the Framingham Heart Study [FHS]) show high heritability of hallux valgus, especially in women. We now have the unique opportunity to link data on specific foot disorders and foot biomechanics to a wealth of genetic data in the FHS and the Johnston County OA Project (JoCo OA), two community-based cohorts. By identifying genetic links to foot disorders which can cause functional limitations in later life, targeted preventive interventions can be applied with the goal of preventing or slowing functional loss. The primary objective of this proposed study is to identify genetic determinants of hallux valgus, pes planus, pes cavus, lesser toe deformities (hammer toes, claw toes, or overlapping toes), and foot biomechanics measures: the Center of Pressure Excursion Index (CPEI), and peak plantar load. Specifically, we propose to 1) expand our knowledge of the heritability of these specific foot traits in the FHS; 2) perform a GWAS meta-analysis to identify genetic variants; and 3) replicate the findings in independent samples. Heritability of foot biomechanics measurements will be estimated in the FHS using pedigree structure by a variance component analysis. A GWAS meta-analysis on foot disorders and biomechanics will combine results from FHS and JoCo OA studies (Caucasians) and then replicate (in-silico) the Single Nucleotide Polymorphisms (SNPs) with association test p-values less than 10-5 for available phenotypes in the Genetics of Generalized Osteoarthritis (GOGO) Study (Caucasians). To assess the generalizability of our findings, we will perform association analysis for those SNPs located in the replicated genome-wide associated regions/loci, in African Americans in JoCo OA. The proposed work involves secondary data analysis, using foot disorders and biomechanical traits from our current NIH-funded Study (RO1 AR047853) using identical protocols in both cohorts. This proposal leverages existing unique clinical, epidemiological, biomechanical and genetic data from two large, long-standing community-based cohorts. The proposal capitalizes upon well-established collaborations between productive epidemiologic, biomechanics, and genetics investigators and (to our knowledge) the only data sources of both specific, valid foot data and well-characterized genetic data. These investigators are thus uniquely poised to examine the genetics of foot disorders in adults. PUBLIC HEALTH RELEVANCE: Foot disorders are extremely common in the population and contribute to disability and diminished quality of life. Many of these run in families, suggesting a genetic origin. It is important to identify those who have these conditions, or are at high risk to develop them, because effective interventions exist and can be targeted to appropriate individuals to lessen their impact or potentially prevent their development.